small molecule antidote for anticoagulantsperospherepharma.com/pdf/per977_aha-presentation.pdf ·...

© 2012 PEROSPHERE INC. 1 © 11/11

CONFIDENTIAL

1 © 11/11

CONFIDENTIAL

Small Molecule Antidote for Anticoagulants

Bryan Laulicht, Sasha Bakhru, Connie Lee,

Christopher Baker, Xuan Jiang, Edith Mathiowitz, James Costin and

Solomon Steiner

AHA, Los Angeles, CA Nov 5, 2012

© 2012 PEROSPHERE INC. 2

Disclosures •  Bryan Laulicht, Sasha Bakhru, Connie Lee, Christopher

Baker, Xuan Jiang, James Costin and Solomon Steiner are employees of Perosphere Inc.

•  Edith Mathiowitz is a consultant of Perosphere Inc.

•  All of the Authors own shares and/or options in Perosphere Inc.

© 2012 PEROSPHERE INC. 3

Introduction § PER977 is a synthetic small molecule § As demonstrated by dynamic light scattering (DLS), PER977

directly binds all approved new oral anticoagulants (NOACs): § Dabigatran, rivaroxaban, apixaban and edoxaban

§ Completed 14 day repeat dose PER977 i.v. two species (dog and rat) toxicology study shows no significant adverse events

§ Completed safety study with PER977 + rivaroxaban and PER977 + dabigatran showing no significant adverse events in beagle dogs

§ Completed metabolite identification § No CYP inhibition or metabolism in vitro § Expected to be in clinical trials in Q1 2013

© 2012 PEROSPHERE INC. 4

PER977-apixaban dynamic light scattering (DLS) binding

•  PER977 binds apixaban at a mass ratio of 1:1 :: PER977:apixaban

0 10 20 30 40

0.1 1 10 100 1000

Volu

me

(%)

Diameter (nm) PER977 Apixaban 1:1 :: PER977:Apixaban 10:1 :: PER977:Apixaban

© 2012 PEROSPHERE INC. 5

Factor Xa or IIa

PER977 competitively binds new oral anticoagulants (NOACs) restoring blocked coagulation factor activity

PER977

Reversal: Factor Xa or IIa activity restored when PER977 binds NOAC

NOAC Xarelto®

Anticoagulation: Factor Xa or IIa activity inhibited by NOAC

NOAC

Factor Xa or IIa

© 2012 PEROSPHERE INC. 6

Overview PER977: § Reduces blood loss and bleeding time, reversing the

anticoagulant activity of dabigatran, rivaroxaban, apixaban and edoxaban in rat tail transection and incision assays

§ Reversal confirmed by aPTT and Xa assays in human blood ex vivo

§ PER977 alone has no dose-dependent effect on coagulation (by platelet aggregation or TEG) ex vivo

§ Presence of rivaroxaban or dabigatran delays PER977 metabolism and increases the MTD of PER977 in blood serum (rats)

© 2012 PEROSPHERE INC. 7

12.5mg PER977 reduces blood loss in dabigatran (15mg p.o.) treated rats to normal levels

§  Full  reversal  at  a  dose  mass  ra.o  of  0.83:1,  N=3  **p<0.01  ***p<0.001  

0  

100  

200  

300  

400  

500  

0   5   12.5   Sham  

5 mg PER977 NO PER977 12.5 mg PER977

Blo

od lo

ss [m

g]

PER977 [mg]

***

*** **

No anticoagulant control

© 2012 PEROSPHERE INC. 8

12.5mg PER977 reduces blood loss in rivaroxaban (2mg p.o.) treated rats to normal levels

0

100

200

300

400

500

0 2.5 12.5 Sham

Blo

od lo

ss [m

g]

PER977 [mg]

*

§  Full  reversal  at  a  dose  mass  ra.o  of  6.25:1,  N=3  *p<0.05  

2.5 mg PER977 NO PER977 12.5 mg PER977

No anticoagulant control

© 2012 PEROSPHERE INC. 9

5mg PER977 reduces blood loss in apixaban (1.25mg p.o.) treated rats to normal levels

§  Full  reversal  at  a  dose  mass  ra.o  of  4:1,  N=3  ***p<0.001  

Blo

od lo

ss [m

g]

PER977 [mg]

***

0

200

400

600

800

0 5 12.5 Sham

5 mg PER977 NO PER977 12.5 mg PER977

No anticoagulant control

© 2012 PEROSPHERE INC. 10

PER977 (12.5 mg) reduces blood loss in edoxaban (5 mg p.o.) treated rats to normal levels

NO PER977 12.5mg PER977

§  Full  reversal  at  a  dose  mass  ra.o  of  2.5:1,  N=5  **p<0.01,  ***p<0.001  

0

100

200

300

400

500

0 31.25 sham

Blo

od lo

ss [m

g]

PER977 [mg]

*** **

12.5 No anticoagulant control

© 2012 PEROSPHERE INC. 11

50

150

250

350

15 25 35 45 55

Ble

edin

g tim

e (s

)

Minutes post PER977 dose

PER977 reversal

0.9% injection saline (sham)

Baseline

*** ♯♯

*** ♯♯

** ♯♯♯

PER977 dabigatran reversal is confirmed by a rat tail incision bleeding time model

** p<0.01, ***p<0.001 compared to PER977 group

♯♯ p<0.01, ♯♯♯ p<0.001 compared to baseline (pre-dose bleeding time)

 "

50

150

250

350

15 25 35 45 55

Ble

edin

g tim

e (s

)

Minutes post PER977 dose

PER977 reversal

0.9% injection saline (sham)

Baseline

***"♯♯"

***"♯♯"

**"♯♯♯"

 "

50

150

250

350

15 25 35 45 55

Ble

edin

g tim

e (s

)

Minutes post PER977 dose

PER977 reversal

0.9% injection saline (sham)

Baseline

***"♯♯"

***"♯♯"

**"♯♯♯"

© 2012 PEROSPHERE INC. 12

0  

10  

20  

30  

40  

50  

60  

70  

Saline  sham   0.25μg/ml  Xarelto®  

0.25μg/ml  Xarelto®  +  50μg/ml  PER977  

 50μg/ml  PER977  

aPTT  [s]  

APTT testing confirms PER977 reverses rivaroxaban in fresh human whole blood ex vivo

rivaroxaban rivaroxaban

© 2012 PEROSPHERE INC. 13

0  

50  

100  

150  

200  

250  

300  

350  

218μg/L  Xarelto®  

218μg/L  Xarelto®  +  1.25μg/L  PER977  

218μg/L  Xarelto®  +  12.5μg/L  PER977  

218μg/L  Xarelto®  +  125μg/L  PER977  

218μg/L  Xarelto®  +  1,250μg/L  PER977  

Effec.v

e  riv

aroxab

an  con

centra.o

n  [μg/L]  

PER977 restores Factor Xa activity in a dose-dependent fashion ex vivo in human plasma

MEC

PER977 restores Xa activity to an effective rivaroxaban concentration below MEC

rivaroxaban rivaroxaban rivaroxaban rivaroxaban rivaroxaban

© 2012 PEROSPHERE INC. 14

PER977 alone shows no dose-dependent effects on platelet aggregation in human blood ex vivo

Agg

rega

tion

ohm

s 10

µM A

DP

Agg

rega

tion

ohm

s 5µ

G/m

L C

olla

gen

50

40

30

20

10

0 0 0.5 5 50

µM PER977 0 0.5 5 50

µM PER977

80

60

40

20

© 2012 PEROSPHERE INC. 15

PER977 alone shows no dose-dependent effects on thromboelastography (TEG) ex vivo

0 0.5 5 50 µM PER977 0 0.5 5 50 µM PER977

0 0.5 5 50 µM PER977 0 0.5 5 50 µM PER977

TEG

R [m

in]

TEG

K [m

in]

TEG

ang

le [d

eg]

TEG

MA

[min

]

2

4

6

8

10

2

4

6

20

40

60

80

20

40

60

80

© 2012 PEROSPHERE INC. 16

PER977

Metabolizing Enzyme

PER977

NOAC

Metabolizing Enzyme

X

Metabolism of PER977 occurs in the blood

Metabolism of PER977 in the blood is slowed in the presence of new oral anticoagulants (NOACs)

PER977

NOAC

Metabolizing Enzyme

X

PER977

NOAC

Metabolizing Enzyme

X

© 2012 PEROSPHERE INC. 17

0.5

1

1.5

2

PER977 PER977 + rivaroxaban

PER977 + dabigatran

Rel

ativ

e se

rum

hal

f-life

NOAC increases the clearance half-life of PER977 in blood serum

§  PER977-NOAC complex is protected from enzymatic metabolism

© 2012 PEROSPHERE INC. 18

NOAC increases the maximally tolerated dose (MTD) of PER977 in rats

§  Toxicologic effects of high doses of PER977 are reduced in the presence of NOAC, further evidencing complex formation

0

0.5

1

1.5

2

PER977 PER977 + Rivaroxaban

PER977 + Apixaban

Rel

ativ

e M

TD

© 2012 PEROSPHERE INC. 19

Review PER977 is a synthetic small molecule that:

§ Reduces blood loss and bleeding time, reversing the anticoagulant activity of dabigatran, rivaroxaban, apixaban and edoxaban in rat tail transection and incision assays

§ Reversal confirmed by aPTT and Xa assays in human blood ex vivo § PER977 alone has no dose-dependent effect on coagulation § Presence of rivaroxaban or dabigatran delays PER977 metabolism in

blood serum and increases the MTD of PER977 (rats) § Completed 14 day repeat dose PER977 i.v. two species (dog and rat)

toxicology study shows no significant adverse events § Completed safety study with PER977 + rivaroxaban and PER977 +

dabigatran showing no significant adverse events in beagle dogs § No CYP inhibition or metabolism in vitro § Expected to be in clinical trials in Q1 2013

© 2012 PEROSPHERE INC. 20

Thank you!

For more information please contact: Dr. Solomon Steiner, CEO (914) 241-0191 S.Steiner@Perosphere.com